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J. Biol. Chem., Vol. 282, Issue 4, 2203-2210, January 26, 2007

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Hu Proteins Regulate Polyadenylation by Blocking Sites Containing U-rich Sequences^*

Hui Zhu¹, Hua-Lin Zhou, Robert A. Hasman, and Hua Lou^¶2

From the Department of Genetics, Case Comprehensive Cancer Center, ^¶The Center for RNA Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

A recent genome-wide bioinformatic analysis indicated that 54% of human genes undergo alternative polyadenylation. Although it is clear that differential selection of poly(A) sites can alter gene expression, resulting in significant biological consequences, the mechanisms that regulate polyadenylation are poorly understood. Here we report that the neuron-specific members of a family of RNA-binding proteins, Hu proteins, known to regulate mRNA stability and translation in the cytoplasm, play an important role in polyadenylation regulation. Hu proteins are homologs of the Drosophila embryonic lethal abnormal visual protein and contain three RNA recognition motifs. Using an in vitro polyadenylation assay with HeLa cell nuclear extract and recombinant Hu proteins, we have shown that Hu proteins selectively block both cleavage and poly(A) addition at sites containing U-rich sequences. Hu proteins have no effect on poly(A) sites that do not contain U-rich sequences or sites in which the U-rich sequences are mutated. All three RNA recognition motifs of Hu proteins are required for this activity. Overexpression of HuR in HeLa cells also blocks polyadenylation at a poly(A) signal that contains U-rich sequences. Hu proteins block the interaction between the polyadenylation cleavage stimulation factor 64-kDa subunit and RNA most likely through direct interaction with poly(A) cleavage stimulation factor 64-kDa subunit and cleavage and polyadenylation specificity factor 160-kDa subunit. These studies identify a novel group of mammalian polyadenylation regulators. Furthermore, they define a previously unknown nuclear function of Hu proteins.

Received for publication, October 3, 2006 , and in revised form, November 22, 2006.

^* This work was supported by American Heart Association Grant 0365274B, National Science Foundation Grant MCB-0237685, and National Institutes of Health Grant NS-049103-01 (to H. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a predoctoral fellowship from the American Heart Association.

² To whom correspondence should be addressed: Dept. of Genetics, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44122. Tel.: 216-368-6419; Fax: 216-368-0491; E-mail: hxl47{at}case.edu.

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